CN106349160B - A kind of 8-aminoquinoline derivatives and its preparation and application - Google Patents
A kind of 8-aminoquinoline derivatives and its preparation and application Download PDFInfo
- Publication number
- CN106349160B CN106349160B CN201610640635.7A CN201610640635A CN106349160B CN 106349160 B CN106349160 B CN 106349160B CN 201610640635 A CN201610640635 A CN 201610640635A CN 106349160 B CN106349160 B CN 106349160B
- Authority
- CN
- China
- Prior art keywords
- formula
- phenyl
- copper
- alkyl
- eluent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
- C07D215/40—Nitrogen atoms attached in position 8
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Quinoline Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a kind of 8-aminoquinoline derivatives and its preparation with prepare anti-malarial, the application in anti-tumor drug, operating process is simple, efficiently, fast, raw material is easy to get, anti-malarial activity (IC50 < 0.1 μM) improves six times or more than (IC50=0.64 μM) of 8- aminoquinoline, and anti-tumor activity improves 10 times or more.R in formula (I)1Replace alkyl for phenyl, substituted-phenyl, C5-C6 aromatic ring, C1-C10 alkyl, C1-C10 alkoxy or C1-C10, the substituent group of the substituted-phenyl is methyl, chlorine, nitro, fluorine or methoxyl group；The substitution alkyl is leucine -5- nitrine quinoline；R2For H or methyl；R3For-N3、‑NH2OrR4For phenyl, C5-C6 aromatic ring or C1-C10 alkyl.
Description
(1) technical field
The present invention relates to a kind of 8-aminoquinoline derivatives, in particular to a kind of 8-aminoquinoline derivatives and its preparation with
Using.
(2) background technique
Malaria (malaria) is the one kind for causing malaria worm to parasitize human body by malaria sting or blood born
Infectious disease, according to World Health Organization's data, malaria is to be only second to AIDS, the big infectious disease in third place in the world lungy.Malaria
Have the characteristics that high incidence, high lethal volume, in history to people with great disaster.According to statistics, the whole world every year have by
Nearly 500,000,000 people is infected with malaria, and causes more than 100 ten thousand people dead.Malaria Major Epidemic and third world countries, especially central africa,
These impoverished nations of South Asia.Disaster and pain greatly are brought to local people.It is main currently used for antimalarial drug
There are qinghaosu and quinolines.Wherein quinolines are not only effectively but also more cheap relative to other class Anti-Malarials,
Due to its being widely used in African Territories, many anti-medicine diseased plants are produced, and cracking spread to the whole world elsewhere.Cause
This explores new anti-malaria medicaments, especially to the modification again of existing 8- aminoquinolines anti-malaria medicaments already at
For the new direction of drug expert research.In addition, 8- aminoquinoline is as a kind of effective pharmaceutical intermediate, in anti-tumor drug
There is potential application value in research and development, active compound especially is carried out to 8- aminoquinoline, being reported, it is certain to possess
Anti-tumor activity.
The method that tradition modifies quinolines is generally required through very long step, stringent condition and low production
Slightly, these existing difficulties greatly reduce for Novel antimalaria drugs progress of research, and increase its research cost
And difficulty.
Therefore, a kind of more quick, sensitive, effective anti-malaria medicaments method of modifying and Novel antimalaria drugs are designed
It is reasonably necessary and urgent, and popular direction of the C-H activating technology as chemical research in recent years, in view of C-H activating technology
Simply, efficient, convenient, and the concern for the person that more and more causes drug research.Although having at present some by C-H activating technology
To the method that 8- aminoquinolines drug is modified, but its preparation is all complex, and higher cost, lacks a kind of letter
Single, effective method of modifying.
(3) summary of the invention
It is an object of the present invention to provide a kind of 8- aminoquinoline (nitrine and triazole) derivative and its preparation and application, no
Only structure novel, and only need a step can high yield be made nitrine analog derivative, it is simple, efficient, convenient to have the characteristics that.
The technical solution adopted by the present invention is that:
The present invention provides 8-aminoquinoline derivatives shown in a kind of formula (I),
R in formula (I)1It is taken for phenyl, substituted-phenyl, C5-C6 aromatic ring, C1-C10 alkyl, C1-C10 alkoxy or C1-C10
Substituted alkyl, the substituent group of the substituted-phenyl are methyl, chlorine, nitro, fluorine or methoxyl group；The C1-C10 replaces alkyl to be bright ammonia
Acid -5- nitrine quinoline；
R2For H or methyl；
R3For-N3、-NH2OrR4For phenyl, C5-C6 aromatic ring or C1-C10 alkyl.
Further, the R1For phenyl, aminomethyl phenyl, p-methylphenyl, rubigan, p-nitrophenyl, adjacent fluorobenzene
Base, p-methoxyphenyl, C6 fat ring group, C4 fatty alkyl, C4 alkoxy or leucine.
Further, more preferably the derivative is one of following:
Work as R3For-N3When, the present invention provides a kind of preparation method of 8-aminoquinoline derivatives, the method are as follows: will
Compound n,N-Dimethylformamide shown in formula (II) and water dissolution, are added nitrine source, and oxidant and copper catalyst constitute anti-
System is answered, saturation NaCl aqueous solution is added after 40 DEG C of fully reactings (preferably 12h), in reaction solution, is extracted with dichloromethane, has taken
Machine layer is dry by magnesium sulfate, filter, solvent is evaporated off to get crude product in rotation under room temperature (preferably 60 DEG C)；By crude product into silicagel column
Chromatography, is the ethyl acetate of 1:3-10 and the solution of petroleum ether as mobile phase using volume ratio, and it is 0.3- that Rf value is collected in TLC tracking
Solvent is removed under reduced pressure in 0.5 eluent, the eluent collected, dry, and it is derivative to obtain 8- aminoquinoline shown in formula (I)
Object；The nitrine source is sodium azide or trimethyl silane nitrine, preferably sodium azide；The copper catalyst is copper acetate, iodine
Change cuprous, copper bromide, copper chloride or stannous chloride, preferably copper acetate；The N,N-dimethylformamide volumetric usage is with formula
(II) amount of combinations of materials shown in is calculated as 1~50ml/mmol, preferably 50ml/mmol, and the volumetric usage of the water is with formula (II)
The amount of shown combinations of materials is calculated as 1~50ml/mmol, preferably 50ml/mmol, and the nitrine source, oxidant, auxiliary agent, phase turn
The ratio between amount of combinations of materials shown in shifting catalyst, copper catalyst and formula (II) be 1~5:1~: 6:0.1~2:0.5~3:
0.01~1:1, preferably 3:3:1:1:0.3:1.
R in formula (I)1It is taken for phenyl, substituted-phenyl, C5-C6 aromatic ring, C1-C10 alkyl, C1-C10 alkoxy or C1-C10
Substituted alkyl, the substituent group of the substituted-phenyl are methyl, chlorine, nitro, fluorine or methoxyl group；The C1-C10 replaces alkyl to be bright ammonia
Acid -5- nitrine quinoline；
R2For H or methyl；
R3For-N3；
R in formula (II)1R in same formula (I)1, R2R in same formula (I)2。
Further, in order to improve conversion ratio, auxiliary agent and phase transfer catalyst, the phase are also added in the reaction system
Transfer catalyst is tetrabutylammonium bromide (TBAB), and the auxiliary agent is one of following: acetic acid, potassium carbonate, triethylamine or 1,8- bis-
11 carbon -7- alkene (DBU) of azabicyclic, preferably DBU；The oxidant is potassium peroxydisulfate or manganese dioxide；The auxiliary agent, phase turn
The ratio between shifting catalyst and the amount of combinations of materials shown in formula (II) are 0.1~2:0.5~3:1, preferably 1:1:1.
Work as R3For-NH2When, the present invention provides a kind of preparation method of 8-aminoquinoline derivatives, the method are as follows:
(1) compound n,N-Dimethylformamide shown in formula (II) and water are dissolved, addition nitrine source, oxidant, copper catalyst,
And/or auxiliary agent and phase transfer catalyst constitute reaction system, and after 40 DEG C of fully reactings (preferably 12h), saturation is added in reaction solution
NaCl aqueous solution, is extracted with dichloromethane, and takes to rotate under organic layer dry by magnesium sulfate, filtering, room temperature (preferably 60 DEG C) and steam
Except solvent is to get crude product；By crude product into silica gel column chromatography, it is for the ethyl acetate of 1:3-10 and the solution of petroleum ether with volume ratio
The eluent that Rf value is 0.3-0.5 is collected in mobile phase, TLC tracking, and solvent is removed under reduced pressure in the eluent collected, dry,
Obtain compound；The nitrine source is sodium azide or trimethyl silane nitrine, preferably sodium azide；The phase transfer catalyst
For tetrabutylammonium bromide (TBAB), the auxiliary agent is one of following: acetic acid, potassium carbonate, triethylamine or 1,8- diazabicylo ten
One carbon -7- alkene (DBU), preferably DBU；The oxidant is potassium peroxydisulfate or manganese dioxide；The copper catalyst is copper acetate, iodine
Change cuprous, copper bromide, copper chloride or stannous chloride, preferably copper acetate；The N,N-dimethylformamide volumetric usage is with formula
(II) amount of combinations of materials shown in is calculated as 1~50ml/mmol, preferably 50ml/mmol, and the volumetric usage of the water is with formula (II)
The amount of shown combinations of materials is calculated as 1~50ml/mmol, preferably 50ml/mmol, and the nitrine source, oxidant, auxiliary agent, phase turn
The ratio between amount of combinations of materials shown in shifting catalyst, copper catalyst and formula (II) be 1~5:1~: 6:0.1~2:0.5~3:
0.01~1:1, preferably 3:3:1:1:0.3:1；(2) by step (1) prepare compound tetrahydrofuran and water (preferably deionization
Water) dissolution, NaHS is added, is reacted 4 hours under room temperature (preferably 25 DEG C), it is water-soluble that saturation NaCl is added into reaction solution
Liquid is extracted with dichloromethane, and takes rotation under organic layer dry by magnesium sulfate, filtering, room temperature (preferably 60 DEG C) that solvent is evaporated off, i.e.,
Crude product is obtained, crude product is subjected to silica gel column chromatography, is the ethyl acetate of 1:3 and the solution of petroleum ether as mobile phase using volume ratio, TLC
The eluent that Rf value is 0.3-0.5 is collected in tracking, and solvent is removed under reduced pressure in the eluent collected, dry, obtains formula (I) institute
Show 8-aminoquinoline derivatives；The tetrahydrofuran volumetric usage is calculated as 1 with the amount of step (1) prepare compound substance~
50ml/mmol, preferably 50ml/mmol, the water volume dosage are calculated as 1~50ml/ with the amount of step (1) prepare compound substance
Mmol, preferably 50ml/mmol, the ratio between amount of the NaHS and step (1) prepare compound substance are 1~5:1, preferably 1:
1；
R in formula (I)1It is taken for phenyl, substituted-phenyl, C5-C6 aromatic ring, C1-C10 alkyl, C1-C10 alkoxy or C1-C10
Substituted alkyl, the substituent group of the substituted-phenyl are methyl, chlorine, nitro, fluorine or methoxyl group；The C1-C10 replaces alkyl to be bright ammonia
Acid -5- nitrine quinoline；
R2For H or methyl；
R3For-NH2；
R in formula (II)1R in same formula (I)1, R2R in same formula (I)2。
Work as R3ForR4When for phenyl, C5-C6 aromatic ring or C1-C10 alkyl, the present invention provides a kind of 8- ammonia
The preparation method of base quinoline, the method are as follows: (1) by compound n,N-Dimethylformamide and water shown in formula (II)
(preferably deionized water) dissolution, is added nitrine source, oxidant, copper catalyst and/or auxiliary agent and phase transfer catalyst constitutes reaction
System is added saturation NaCl aqueous solution, is extracted with dichloromethane, takes organic after 40 DEG C of fully reactings (preferably 12h), in reaction solution
Layer is dry by magnesium sulfate, filter, solvent is evaporated off to get crude product in rotation under room temperature；By crude product into silica gel column chromatography, with volume ratio
It is mobile phase for the ethyl acetate of 1:3-10 and the solution of petroleum ether, TLC tracking is collected the eluent that Rf value is 0.3-0.5, received
Collect obtained eluent and solvent is removed under reduced pressure, it is dry, obtain compound；The nitrine source is sodium azide or trimethyl silane
Nitrine, preferably sodium azide；The phase transfer catalyst is tetrabutylammonium bromide (TBAB), and the auxiliary agent is one of following: vinegar
Acid, potassium carbonate, triethylamine or 1,11 carbon -7- alkene (DBU) of 8- diazabicylo, preferably DBU；The oxidant is potassium peroxydisulfate
Or manganese dioxide；The copper catalyst is copper acetate, cuprous iodide, copper bromide, copper chloride or stannous chloride, preferably copper acetate；
The n,N-Dimethylformamide volumetric usage is calculated as 1~50ml/mmol with the amount of combinations of materials shown in formula (II), preferably
The volumetric usage of 50ml/mmol, the water are calculated as 1~50ml/mmol with the amount of combinations of materials shown in formula (II), preferably
50ml/mmol, combinations of materials shown in the nitrine source, oxidant, auxiliary agent, phase transfer catalyst, copper catalyst and formula (II)
The ratio between amount for 1~5:1~: 6:0.1~2:0.5~3:0.01~1:1, preferably 3:3:1:1:0.3:1；(2) step (1) is made
Standby compound tetrahydrofuran and water (preferably deionized water) dissolve, and add phenylacetylene, copper catalyst, anti-under room temperature (25 DEG C)
Answer 12 hours, saturation NaCl aqueous solution be added into reaction solution, is extracted with dichloromethane, take organic layer it is dry by magnesium sulfate,
Solvent is evaporated off to get crude product in rotation under filtering, room temperature, and crude product carries out silica gel column chromatography, with the volume of ethyl acetate and petroleum ether
It is mobile phase than the solution for 1:4, the eluent that Rf value is 0.3-0.5 is collected in TLC tracking, and the eluent collected is through depressurizing
Solvent is removed, it is dry, obtain 8-aminoquinoline derivatives shown in formula (I)；The copper catalyst is copper acetate, cuprous iodide, bromine
Change cuprous or copper chloride, preferably cuprous iodide, partial size 100nm；The tetrahydrofuran volumetric usage prepares chemical combination with step (1)
The amount of object substance is calculated as 1~50ml/mmol, preferably 50ml/mmol, and the water volume dosage is with step (1) prepare compound object
The amount of matter is calculated as 1~50ml/mmol, preferably 50ml/mmol, the phenylacetylene, copper catalyst and step (1) prepare compound object
The ratio between amount of matter is 0.8~2:0.01~1:1, preferably 1:1:1；
R in formula (I)1It is taken for phenyl, substituted-phenyl, C5-C6 aromatic ring, C1-C10 alkyl, C1-C10 alkoxy or C1-C10
Substituted alkyl, the substituent group of the substituted-phenyl are methyl, chlorine, nitro, fluorine or methoxyl group；The C1-C10 replaces alkyl to be bright ammonia
Acid -5- nitrine quinoline；
R2For H or methyl；
R3ForR4For phenyl, C5-C6 aromatic ring or C1-C10 alkyl, preferably phenyl；
R in formula (II)1R in same formula (I)1, R2R in same formula (I)2。
8-aminoquinoline derivatives preparation route of the present invention are as follows:
Auxiliary agent and phase transfer catalyst can not be added in reaction system of the present invention for azido reaction, or
It only adds one such, can also be added with both of which, i.e., reaction system is one of following: (1) formula (II) shown in compound, N,
Dinethylformamide, water, nitrine source, oxidant, copper catalyst；(2) compound, N shown in formula (II), N- dimethyl formyl
Amine, water, nitrine source, oxidant, copper catalyst, auxiliary agent and phase transfer catalyst；(3) compound, N shown in formula (II), N- diformazan
Base formamide, water, nitrine source, oxidant, copper catalyst, auxiliary agent；(4) compound shown in formula (II), N,N-dimethylformamide,
Water, nitrine source, oxidant, copper catalyst and phase transfer catalyst.
In addition, the present invention also provides a kind of 8-aminoquinoline derivatives to prepare the application in anti-malaria medicaments.
The present invention also provides a kind of 8-aminoquinoline derivatives application in preparation of anti-tumor drugs, the tumours
Cell is lung cancer cell line A549, liver cancer cell lines HePG-2.
Compared with the conventional method, its advantages are embodied in the present invention:
(1) the present invention provides a kind of noval chemical compound -8-aminoquinoline derivatives and preparation method thereof, operating process letters
Single, raw material sources have all been commercialized and have been easy to get, and synthesized noval chemical compound, the anti-malarial activity of preferred compound
(IC50 < 0.1 μM) improves six times or more than (IC50=0.64 μM) of 8- aminoquinoline, and anti-tumor activity improves 10 times or more.
(2) more direct compared with pervious to the method for quinoline substance modification modification, efficiently, fast.
(4) specific embodiment
The present invention is described further combined with specific embodiments below, but protection scope of the present invention is not limited in
This:
Below the technical scheme of the invention is illustrated by a specific example, but the scope of the present invention is not limited thereto:
Embodiment 1: preparation N- (5- nitrine quinoline -8- amino) benzamide
0.1mmol N- (- 8 amino of quinoline) benzamide (II -1) is added to the N,N-dimethylformamide and 5ml of 5ml
Mixed liquor 10ml is made in deionized water, 0.3mmol sodium azide, copper acetate 0.03mmol, 0.3mmol over cure are added thereto
Sour potassium, 0.1mmol DBU, 0.1mmol TBAB, 40 DEG C are reacted 12 hours, and saturation NaCl is added after reaction, in reaction solution
Aqueous solution is extracted with dichloromethane, and takes organic layer dry by anhydrous magnesium sulfate, filtering, 60 DEG C of decompression distilleds to remove solvent, i.e.,
Obtain crude compound shown in the formula (I -1).It is 1:5 with volume ratio by crude compound shown in formula (I -1) into silica gel column chromatography
Ethyl acetate and petroleum ether solution be mobile phase, TLC tracking collect Rf value be 0.3-0.5 eluent, collect
Solvent is removed under reduced pressure in eluent, dry, obtains formula (I -1) compound represented sterling 22mg.
1H NMR(500MHz,CDCl3) δ 10.56 (s, 1H), 8.93 (dd, J=10.2,5.4Hz, 1H), 8.84 (dd, J=
4.1,1.2Hz, 1H), 8.39 (dd, J=8.4,1.2Hz, 1H), 8.07 (dd, J=13.8,6.9Hz, 2H), 7.62-7.50 (m,
3H), 7.45 (dd, J=8.4,4.1Hz, 1H), 7.28 (dd, J=7.7,5.3Hz, 1H)13C NMR(126MHz,CDCl3)δ
165.11,149.08,138.99,134.88,131.84,131.52,131.56,130.32,128.76,127.18,121.50,
121.33,116.36,114.84.
Embodiment 2: preparation N- (5- nitrine quinoline -8- amino) -3- methyl-benzamide
0.1mmol N- (- 8 amino of quinoline) -3- methyl benzamide (II-2) is added to the N,N-dimethylformamide of 5ml
With mixed liquor 10ml is made in 5ml deionized water, thereto be added 0.3mmol sodium azide, copper acetate 0.03mmol,
0.3mmol potassium peroxydisulfate, 0.1mmol DBU, 0.1mmol TBAB, 40 DEG C are reacted 12 hours, after reaction, are added in reaction solution
Enter to be saturated NaCl aqueous solution, be extracted with dichloromethane, takes organic layer by anhydrous magnesium sulfate drying, filtering, 60 DEG C of decompression distilleds
Solvent is removed to get crude compound shown in the formula (I -2), crude compound shown in formula (I -2) carries out silica gel column chromatography, with
The solution of ethyl acetate and petroleum ether that volume ratio is 1:10 is mobile phase, and the elution that Rf value is 0.3-0.5 is collected in TLC tracking
Solvent is removed under reduced pressure in liquid, the eluent collected, dry, obtains pure compounds 23mg shown in formula (I -2).
1H NMR(500MHz,CDCl3) δ 10.21 (s, 1H), 8.86 (d, J=8.4Hz, 1H), 8.81 (dd, J=4.2,
1.5Hz, 1H), 8.57 (dd, J=8.5,1.6Hz, 1H), 7.87 (d, J=8.4Hz, 1H), 7.69 (d, J=7.7Hz, 1H),
7.59 (m, J=8.5,4.2Hz, 1H), 7.43 (m, J=7.5,1.3Hz, 1H), 7.34 (t, J=7.9Hz, 2H), 2.61 (s,
3H).13C NMR(126MHz,CDCl3)δ168.16,148.78,139.37,136.81,136.36,136.03,134.70,
131.48,130.97,130.51,127.18,127.46,126.07,122.73,117.04,114.50,20.22.
Embodiment 3: preparation N- (5- nitrine quinoline -8- amino) -4- methyl-benzamide
0.1mmolN- (5- quinoline -8- amino) -4- methyl-benzamide (II-3) is added to the N of 5ml, N- dimethyl methyl
Mixed liquor 10ml is made in amide and 5ml deionized water, thereto addition 0.3mmol sodium azide, copper acetate 0.03mmol,
0.3mmol potassium peroxydisulfate, 0.1mmol DBU, 0.1mmol TBAB, 40 DEG C are reacted 12 hours, after reaction, are added in reaction solution
Enter to be saturated NaCl aqueous solution, be extracted with dichloromethane, takes organic layer by anhydrous magnesium sulfate drying, filtering, 60 DEG C of decompression distilleds
Solvent is removed to get crude compound shown in the formula (I -3), crude compound shown in formula (I -3) carries out column chromatography, with volume
Solution than ethyl acetate and petroleum ether for 1:5 is mobile phase, and TLC tracking is collected the eluent that Rf value is 0.3-0.5, collected
Solvent is removed under reduced pressure in obtained eluent, dry, obtains pure compounds 20mg shown in formula (I -3).
1H NMR(500MHz,CDCl3) δ 10.61 (s, 1H), 8.98 (d, J=8.3Hz, 1H), 8.90 (dd, J=4.2,
1.5Hz, 1H), 8.47 (dd, J=8.4,1.5Hz, 1H), 7.98 (d, J=8.1Hz, 2H), 7.51 (m, J=8.4,4.2Hz,
1H), 7.36 (dd, J=8.1,1.9Hz, 3H), 2.47 (s, 3H)13C NMR(126MHz,CDCl3)δ165.17,149.07,
148.19,142.38,139.05,136.31,132.12,131.58,130.19,129.44,127.22,121.50,116.33,
114.92,21.50.
Embodiment 4: preparation N- (5- nitrine quinoline -8- amino) chloro- benzamide of -4-
0.1mmolN- (5- quinoline -8- amino) the chloro- benzamide of -4- (II-4) is added to the N,N-dimethylformamide of 5ml
Mixed liquor 10ml is made with 5ml deionized water, 0.3mmol sodium azide, copper acetate 0.03mmol, 0.3mmol are added thereto
Potassium peroxydisulfate, 0.1mmol DBU, 0.1mmol TBAB, 40 DEG C are reacted 12 hours, after reaction, saturation are added in reaction solution
NaCl aqueous solution, is extracted with dichloromethane, and takes organic layer dry by anhydrous magnesium sulfate, filtering, 60 DEG C of decompression distilleds removings molten
Agent is to get crude compound shown in the formula (I -4), and (I -4) crude compound shown in formula carries out silica gel column chromatography, with volume ratio
It is mobile phase for the ethyl acetate of 1:8 and the solution of petroleum ether, TLC tracking is collected the eluent that Rf value is 0.3-0.5, collected
To eluent solvent is removed under reduced pressure, it is dry, obtain pure compounds 25mg shown in formula (I -4).
1H NMR(500MHz,CDCl3) δ 10.61 (s, 1H), 8.95 (d, J=8.4Hz, 1H), 8.91 (dd, J=4.2,
1.6Hz, 1H), 8.48 (dd, J=8.5,1.6Hz, 1H), 8.04 (m, 2H), 7.54 (m, 3H), 7.37 (d, J=8.4Hz, 1H)
.13C NMR(126MHz,CDCl3)δ164.26,148.32,138.70,138.10,136.40,134.33,133.51,
129.02,128.69,127.97,127.41,121.80,121.67,116.59.
Embodiment 5: preparation N- (5- nitrine quinoline -8- amino) -4- nitro-phenacetyl amine
By 0.1mmolN- (5- quinoline -8- amino) -4- nitro-phenacetyl amine (II-5), the n,N-Dimethylformamide of 5ml
Mixed liquor 10ml is made with 5ml deionized water, 0.3mmol sodium azide, copper acetate 0.03mmol, 0.3mmol are added thereto
Potassium peroxydisulfate, 0.1mmol DBU, 0.1mmol TBAB, 40 DEG C are reacted 12 hours, after reaction, saturation are added in reaction solution
NaCl aqueous solution, is extracted with dichloromethane, and takes organic layer dry by anhydrous magnesium sulfate, filtering, 60 DEG C of decompression distilleds removings molten
Agent is to get crude compound shown in the formula (I -5), and crude compound shown in formula (I -5) carries out silica gel column chromatography, with volume ratio
It is mobile phase for the ethyl acetate of 1:8 and the solution of petroleum ether, TLC tracking is collected the eluent that Rf value is 0.3-0.5, collected
To eluent solvent is removed under reduced pressure, it is dry, obtain pure compounds 24mg shown in formula (I -5).
1H NMR(500MHz,CDCl3) δ 10.06 (s, 1H), 8.92 (d, J=8.3Hz, 1H), 8.81 (dd, J=4.1,
1.5Hz, 1H), 8.47 (dd, J=8.5,1.5Hz, 1H), 8.16 (d, J=8.2Hz, 1H), 7.79 (m, J=6.7,3.8Hz,
2H), 7.69 (m, J=8.7,5.8,3.2Hz, 1H), 7.50 (dd, J=8.4,4.2Hz, 1H), 7.37 (d, J=8.3Hz, 1H)
.13C NMR(126MHz,CDCl3)δ164.10,149.28,148.38,146.83,138.83,136.48,133.83,
131.81,130.90,128.67,124.83,121.72,117.10,114.89.
Embodiment 6: preparation N- (5- nitrine quinoline -8- amino) fluoro- benzamide of -2-
By 0.1mmolN- (5- quinoline -8- amino) the fluoro- benzamide of -2- (II-6), the n,N-Dimethylformamide of 5ml and
Mixed liquor 10ml is made in 5ml deionized water, and 0.3mmol sodium azide, copper acetate 0.03mmol, 0.3mmol mistake are added thereto
Potassium sulfate, 0.1mmol DBU, 0.1mmol TBAB, 40 DEG C are reacted 12 hours, after reaction, saturation are added in reaction solution
NaCl aqueous solution, is extracted with dichloromethane, and takes organic layer dry by anhydrous magnesium sulfate, filtering, 60 DEG C of decompression distilleds removings molten
Agent is to get crude compound shown in the formula (I -6), and crude compound shown in formula (I -6) carries out silica gel column chromatography, with volume ratio
It is mobile phase for the ethyl acetate of 1:10 and the solution of petroleum ether, TLC tracking is collected the eluent that Rf value is 0.3-0.5, collected
Solvent is removed under reduced pressure in obtained eluent, dry, obtains pure compounds 26mg shown in formula (I -6).
1H NMR(500MHz,CDCl3) δ 10.05 (s, 1H), 8.95 (d, J=8.3Hz, 1H), 8.80 (dd, J=4.2,
1.6Hz, 1H), 8.46 (dd, J=8.5,1.6Hz, 1H), 7.82 (d, J=7.8Hz, 1H), 7.78 (d, J=7.5Hz, 1H),
7.71 (t, J=7.4Hz, 1H), 7.64 (t, J=7.7Hz, 1H), 7.49 (m, J=8.5,4.2Hz, 1H), 7.35 (d, J=
8.3Hz,1H).13C NMR(126MHz,CDCl3)δ165.76,149.26,138.88,136.04,132.20,131.70,
131.38,131.14,130.22,128.56,127.83,126.73,121.66,121.46,116.88,114.84.
Embodiment 7: preparation N- (5- nitrine quinoline -8- amino) -4- methoxyl group-benzamide
By 0.1mmolN- (5- quinoline -8- amino) -4- methoxyl group-benzamide (II-7), the N of 5ml, N- dimethyl formyl
Mixed liquor 10ml is made in amine and 5ml deionized water, thereto addition 0.3mmol sodium azide, copper acetate 0.03mmol,
0.3mmol potassium peroxydisulfate, 0.1mmol DBU, 0.1mmol TBAB, 40 DEG C are reacted 12 hours, after reaction, are added in reaction solution
Enter to be saturated NaCl aqueous solution, be extracted with dichloromethane, takes organic layer by anhydrous magnesium sulfate drying, filtering, 60 DEG C of decompression distilleds
Solvent is removed to get crude compound shown in the formula (I -7), crude compound shown in formula (I -7) is into silica gel column chromatography, with body
Product ratio is the ethyl acetate of 1:10 and the solution of petroleum ether is mobile phase, and the eluent that Rf value is 0.3-0.5 is collected in TLC tracking,
It collects obtained eluent and solvent is removed under reduced pressure, it is dry, obtain pure compounds 19mg shown in formula (I -7).
1H NMR(500MHz,CDCl3) δ 10.57 (s, 1H), 8.97 (d, J=4.3,1H), 8.90 (dd, J=4.2,
1.6Hz, 1H), 8.47 (dd, J=8.5,1.6Hz, 1H), 8.08 (m, 2H), 7.52 (m, J=8.5,4.2Hz, 1H), 7.36 (d,
J=8.4Hz, 1H), 7.06 (d, J=8.8Hz, 2H), 3.92 (s, 3H)13C NMR(126MHz,CDCl3)δ162.62,
149.13,148.24,142.39,139.19,131.83,131.65,130.20,129.19,129.37,127.34,121.56,
121.23,116.36,115.10,114.05,55.51.
Embodiment 8: preparation N- (5- nitrine quinoline -8- amino)-cyclohexyl amide
By 0.1mmolN- (5- quinoline -8- amino)-cyclohexyl amide (II-8), the n,N-Dimethylformamide of 5ml and
Mixed liquor 10ml is made in 5ml deionized water, and 0.3mmol sodium azide, copper acetate 0.03mmol, 0.3mmol mistake are added thereto
Potassium sulfate, 0.1mmol DBU, 0.1mmol TBAB, 40 DEG C are reacted 12 hours, after reaction, saturation are added in reaction solution
NaCl aqueous solution, is extracted with dichloromethane, and takes organic layer dry by anhydrous magnesium sulfate, filtering, 60 DEG C of decompression distilleds removings molten
Agent is to get crude compound shown in the formula (I -8), and crude compound shown in formula (I -8) carries out silica gel column chromatography, with volume ratio
It is mobile phase for the ethyl acetate of 1:5 and the solution of petroleum ether, TLC tracking is collected the eluent that Rf value is 0.3-0.5, collected
To eluent solvent is removed under reduced pressure, it is dry, obtain pure compounds 20mg shown in formula (I -8).
1H NMR(500MHz,CDCl3) δ 9.78 (s, 1H), 8.91 (m, 2H), 8.44 (dd, J=8.5,1.6Hz, 1H),
7.49 (dd, J=8.5,4.2Hz, 1H), 7.30 (d, J=8.4Hz, 1H), 2.48 (m, J=11.8,3.5Hz, 1H), 2.10 (d,
J=15.2Hz, 2H), 1.94 (m, 2H), 1.76 (d, J=11.8Hz, 1H), 1.65 (dd, J=12.3,2.9Hz, 2H), 1.45
(m,3H).13C NMR(126MHz,CDCl3)δ174.79,149.02,138.90,131.73,131.68,130.03(s),
121.46,121.23,116.38,115.02,77.29,77.04,76.78,46.88,29.78,25.78.
Embodiment 9: preparation N- (5- nitrine quinoline -8- amino)-pentanamide
By 0.1mmolN- (5- quinoline -8- amino)-pentanamide (II-9), n,N-Dimethylformamide 5ml and deionized water
Mixed liquor 10ml is made in 5ml, thereto addition 0.3mmol sodium azide, copper acetate 0.03mmol, 0.3mmol potassium peroxydisulfate,
0.1mmol DBU, 0.1mmol TBAB, 40 DEG C are reacted 12 hours, and it is water-soluble that saturation NaCl is added after reaction, in reaction solution
Liquid is extracted with dichloromethane, and organic layer dry by anhydrous magnesium sulfate, filtering, 60 DEG C of decompression distilleds is taken to remove solvent to get institute
Crude compound shown in formula (I -9) is stated, it is the second of 1:5 with volume ratio that crude compound shown in formula (I -9), which carries out silica gel column chromatography,
The solution of acetoacetic ester and petroleum ether is mobile phase, and the eluent that Rf value is 0.3-0.5, the elution collected are collected in TLC tracking
Solvent is removed under reduced pressure in liquid, dry, obtains pure compounds 18mg shown in formula (I -9).
1H NMR(500MHz,CDCl3) δ 9.70 (s, 1H), 8.87 (m, 2H), 8.44 (dd, J=8.5,1.5Hz, 1H),
7.49 (dd, J=8.5,4.2Hz, 1H), 7.30 (d, J=8.4Hz, 1H), 2.60 (m, 2H), 1.81 (m, J=15.2,7.6Hz,
2H), 1.48 (m, 2H), 1.00 (t, J=7.4Hz, 3H)13C NMR(126MHz,CDCl3)δ171.73,147.96,138.22,
136.18,134.48,127.81,127.27,121.41,121.18,116.26,37.85,27.63,22.32,13.73.
Embodiment 10: tert-butyl-(5- nitrine quinoline -8-) carbonic acid amide is prepared
By 0.1mmol tert-butyl--8 carbonic acid amide of quinoline (II-10), it is dissolved in n,N-Dimethylformamide 5ml and deionization
Mixed liquor 10ml is made in water 5ml, thereto addition 0.3mmol sodium azide, 0.3mmol potassium peroxydisulfate, copper acetate 0.03mmol,
0.1mmol DBU, 0.1mmol TBAB, 40 DEG C are reacted 12 hours, and it is water-soluble that saturation NaCl is added after reaction, in reaction solution
Liquid is extracted with dichloromethane, and organic layer dry by anhydrous magnesium sulfate, filtering, 60 DEG C of decompression distilleds is taken to remove solvent to get institute
Crude compound shown in formula (I -10) is stated, it is 1:5's with volume ratio that crude compound shown in formula (I -10), which carries out silica gel column chromatography,
The solution of ethyl acetate and petroleum ether is mobile phase, and the eluent that Rf value is 0.3-0.5 is collected in TLC tracking, and that collects washes
Solvent is removed under reduced pressure in de- liquid, dry, obtains pure compounds 8.1mg shown in formula (I -10).
1H NMR(500MHz,CDCl3) δ 8.88 (dd, J=4.2,1.6Hz, 1H), 8.82 (s, 1H), 8.33 (dd, J=
8.5,1.6Hz, 1H), 8.22 (d, J=8.4Hz, 1H), 7.61 (m, J=8.5,4.2Hz, 1H), 7.42 (d, J=8.4Hz,
1H),1.46(s,9H).13C NMR(126MHz,CDCl3)δ152.76,147.85,138.13,136.11,135.09,
127.96,127.18,121.41,120.06,114.29,80.24,28.28.
Embodiment 11:
N-Fmoc- leucine -5- nitrine quinoline -8- amide
By 0.1mmol N-Fmoc- leucine -5- quinoline -8- amide (II-11), the N of 5ml, N- dimethyl formyl is added
Mixed liquor 10ml is made in amine and 5ml deionized water, thereto addition 0.3mmol sodium azide, copper acetate 0.03mmol,
0.3mmol potassium peroxydisulfate, 0.1mmol DBU, 0.1mmol TBAB, 40 DEG C are reacted 12 hours, after reaction, are added in reaction solution
Enter to be saturated NaCl aqueous solution, be extracted with dichloromethane, takes organic layer by anhydrous magnesium sulfate drying, filtering, 60 DEG C of decompression distilleds
Solvent is removed to get crude compound shown in the formula (I -11), crude compound shown in formula (I -11) carries out silica gel column chromatography,
It is the ethyl acetate of 1:3 and the solution of petroleum ether as mobile phase using volume ratio, the elution that Rf value is 0.3-0.5 is collected in TLC tracking
Solvent is removed under reduced pressure in liquid, the eluent collected, dry, obtains formula (I -11) compound represented sterling 15mg.
1H NMR(500MHz,CDCl3) δ 10.06 (s, 1H), 8.79 (d, J=8.4Hz, 2H), 8.44 (dd, J=8.5,
1.5Hz, 1H), 7.79 (t, J=6.6Hz, 3H), 7.64 (m, J=7.4Hz, 2H), 7.48 (m, J=8.4,4.2Hz, 1H),
7.41 (d, J=7.1Hz, 2H), 7.32 (m, 3H), 5.60 (d, J=8.3Hz, 1H), 4.42 (m, J=21.0,7.1Hz, 2H),
4.28 (t, J=6.8Hz, 1H), 4.08 (d, J=5.2Hz, 1H), 1.08 (m, J=15.4,6.6Hz, 6H)13C NMR
(126MHz,CDCl3)δ169.84,148.48,143.80,141.34,138.56,136.33,133.87,127.98,
127.72,127.29,127.09,125.18,124.72,122.06,121.75,120.00,116.72,67.18,61.46,
47.30,31.69,19.30,17.90.
Embodiment 12: preparation N- (5- nitrine -6- methylquinoline -8- amino) benzamide
By 0.1mmolN- (6- methylquinoline -8- amino) benzamide (II-12), it is dissolved in the n,N-Dimethylformamide of 5ml
Mixed liquor 10ml is made with 5ml deionized water, 0.3mmol sodium azide, copper acetate 0.03mmol, 0.3mmol are added thereto
Potassium peroxydisulfate, 0.1mmol DBU, 0.1mmol TBAB, 40 DEG C are reacted 12 hours, after reaction, saturation are added in reaction solution
NaCl aqueous solution, is extracted with dichloromethane, and takes organic layer dry by anhydrous magnesium sulfate, filtering, 60 DEG C of decompression distilleds removings molten
Agent is to get crude compound shown in the formula (I -12), and crude compound shown in formula (I -12) carries out silica gel column chromatography, with volume
Solution than ethyl acetate and petroleum ether for 1:10 is mobile phase, and TLC tracking is collected the eluent that Rf value is 0.3-0.5, received
Collect obtained eluent and solvent is removed under reduced pressure, it is dry, obtain pure compounds 24mg shown in formula (I -12).
1H NMR(500MHz,CDCl3) δ 10.65 (s, 1H), 8.84 (t, J=2.8Hz, 2H), 8.54 (dd, J=8.5,
1.5Hz,1H),8.11(m,2H),7.58(m,4H),2.67(s,3H).13C NMR(126MHz,CDCl3)δ165.42,
147.36,137.60,137.63,135.62,135.20,134.14,131.80,128.79,128.05,127.28,121.71,
120.63,118.63,22.35. embodiment 13:
N- (5- (4- phenyl-triazol radical)-quinoline -8- amino) benzamide
Compound shown in formula (I -1) prepared by 0.1mmoL embodiment 1, is dissolved in 5ml tetrahydrofuran and 5ml deionized water
In mixed liquor 10ml is made, the phenylacetylene of 0.1mmol, 0.1mmol nanometers of cuprous iodides (partial size 100nm) are added thereto, often
It is reacted 12 hours under warm (25 DEG C), saturation NaCl aqueous solution is added into reaction solution, is extracted with dichloromethane, organic layer is taken to pass through
Anhydrous magnesium sulfate is dry, filter, 60 DEG C of decompression distilleds remove solvents to get crude compound shown in the formula (I-13), formula (I-
13) crude compound shown in carries out silica gel column chromatography, is the ethyl acetate of 1:4 and the solution of petroleum ether as flowing using volume ratio
The eluent that Rf value is 0.3-0.5 is collected in phase, TLC tracking, and solvent is removed under reduced pressure in the eluent collected, dry, is obtained
Pure compounds 32mg shown in formula (I-13).
1H NMR(500MHz,CDCl3) δ 10.90 (s, 1H), 9.10 (d, J=8.3Hz, 1H), 8.98 (dd, J=4.2,
1.5Hz, 1H), 8.65 (d, J=5.3Hz, 1H), 8.34 (m, 2H), 8.15 (m, 2H), 7.87 (m, J=7.8,1.7Hz, 1H),
7.78 (d, J=8.3Hz, 1H), 7.66 (m, 4H), 7.31 (m, J=7.5,4.8,1.0Hz, 1H)13C NMR(126MHz,
CDCl3) δ 165.67,149.94,149.64,149.29,148.62,138.55,137.09,136.53,134.68,132.27,
132.19,128.95,127.40,124.52,124.49,123.69,123.24,123.20,120.53,115.24.
Embodiment 14: preparation N- (5- aminoquinoline -8- amino) benzamide
Compound shown in formula (I-1) prepared by the embodiment 1 of 0.1mmol is dissolved in 5ml tetrahydrofuran and 5ml deionized water
In, the NaHS of 0.1mmol is added thereto, is reacted 4 hours under room temperature (25 DEG C), saturation NaCl water is added into reaction solution
Solution is extracted with dichloromethane, take organic layer dry by anhydrous magnesium sulfate, filtering, 60 DEG C of decompression distilleds removing solvents to get
Crude compound shown in the formula (I-14), crude compound shown in formula (I-14) carry out silica gel column chromatography, are 1:3 with volume ratio
Ethyl acetate and petroleum ether solution be mobile phase, TLC tracking collect Rf value be 0.3-0.5 eluent, collect
Solvent is removed under reduced pressure in eluent, dry, obtains pure compounds 20mg shown in formula (I-14).
1H NMR (500MHz, DMSO) δ 9.02 (s, 1H), 8.85 (dd, J=4.1,1.6Hz, 1H), 8.02 (m, 3H),
7.90 (d, J=8.6Hz, 1H), 7.86 (dd, J=8.6,1.6Hz, 1H), 7.58 (m, 4H), 6.96 (d, J=8.2Hz, 1H),
6.52(s,2H).13C NMR(126MHz,DMSO)δ147.80,147.32,145.28,136.14,130.61,129.50,
129.03,127.01,125.68,124.55,124.10,123.12,119.62,106.39,100.75.
Embodiment 15: preparation N- (5- nitrine quinoline -8- amino) benzamide
0.1mmol N- (- 8 amino of quinoline) benzamide (II -1) is added to the N,N-dimethylformamide and 5ml of 5ml
Mixed liquor 10ml is made in deionized water, 0.3mmol sodium azide, copper acetate 0.03mmol, 0.3mmol over cure are added thereto
Sour potassium, 0.1mmol DBU, 40 DEG C are reacted 12 hours, and saturation NaCl aqueous solution is added after reaction, in reaction solution, uses dichloro
Methane extraction takes organic layer dry by anhydrous magnesium sulfate, filtering, 60 DEG C of decompression distilleds to remove solvent to get the formula (I -1)
Shown crude compound.By crude compound shown in formula (I -1) into silica gel column chromatography, with volume ratio for the ethyl acetate of 1:5 and
The solution of petroleum ether is mobile phase, and the eluent that Rf value is 0.3-0.5 is collected in TLC tracking, and the eluent collected is through depressurizing
Solvent is removed, it is dry, obtain formula (I -1) compound represented sterling 18mg.
1H NMR(500MHz,CDCl3) δ 10.56 (s, 1H), 8.93 (dd, J=10.2,5.4Hz, 1H), 8.84 (dd, J=
4.1,1.2Hz, 1H), 8.39 (dd, J=8.4,1.2Hz, 1H), 8.07 (dd, J=13.8,6.9Hz, 2H), 7.62-7.50 (m,
3H), 7.45 (dd, J=8.4,4.1Hz, 1H), 7.28 (dd, J=7.7,5.3Hz, 1H)13C NMR(126MHz,CDCl3)δ
165.11,149.08,138.99,134.88,131.84,131.52,131.56,130.32,128.76,127.18,121.50,
121.33,116.36,114.84.
Embodiment 16: preparation N- (5- nitrine quinoline -8- amino) benzamide
0.1mmol N- (- 8 amino of quinoline) benzamide (II -1) is added to the N,N-dimethylformamide and 5ml of 5ml
Mixed liquor 10ml is made in deionized water, 0.3mmol sodium azide, copper acetate 0.03mmol, 0.3mmol over cure are added thereto
Sour potassium, 0.1mmol TBAB, 40 DEG C are reacted 12 hours, and saturation NaCl aqueous solution is added after reaction, in reaction solution, uses dichloro
Methane extraction takes organic layer dry by anhydrous magnesium sulfate, filtering, 60 DEG C of decompression distilleds to remove solvent to get the formula (I -1)
Shown crude compound.By crude compound shown in formula (I -1) into silica gel column chromatography, with volume ratio for the ethyl acetate of 1:5 and
The solution of petroleum ether is mobile phase, and the eluent that Rf value is 0.3-0.5 is collected in TLC tracking, and the eluent collected is through depressurizing
Solvent is removed, it is dry, obtain formula (I -1) compound represented sterling 12mg.
1H NMR(500MHz,CDCl3) δ 10.56 (s, 1H), 8.93 (dd, J=10.2,5.4Hz, 1H), 8.84 (dd, J=
4.1,1.2Hz, 1H), 8.39 (dd, J=8.4,1.2Hz, 1H), 8.07 (dd, J=13.8,6.9Hz, 2H), 7.62-7.50 (m,
3H), 7.45 (dd, J=8.4,4.1Hz, 1H), 7.28 (dd, J=7.7,5.3Hz, 1H)13C NMR(126MHz,CDCl3)δ
165.11,149.08,138.99,134.88,131.84,131.52,131.56,130.32,128.76,127.18,121.50,
121.33,116.36,114.84.
Embodiment 17: preparation N- (5- nitrine quinoline -8- amino) benzamide
0.1mmol N- (- 8 amino of quinoline) benzamide (II -1) is added to the N,N-dimethylformamide and 5ml of 5ml
Mixed liquor 10ml is made in deionized water, 0.3mmol sodium azide, cuprous iodide 0.03mmol, 0.3mmol mistake are added thereto
Potassium sulfate, 0.1mmol DBU, 0.1mmol TBAB, 40 DEG C are reacted 12 hours, after reaction, saturation are added in reaction solution
NaCl aqueous solution, is extracted with dichloromethane, and takes organic layer dry by anhydrous magnesium sulfate, filtering, 60 DEG C of decompression distilleds removings molten
Agent is to get crude compound shown in the formula (I -1).By crude compound shown in formula (I -1) into silica gel column chromatography, with volume ratio
It is mobile phase for the ethyl acetate of 1:5 and the solution of petroleum ether, TLC tracking is collected the eluent that Rf value is 0.3-0.5, collected
To eluent solvent is removed under reduced pressure, it is dry, obtain formula (I -1) compound represented sterling 18mg.
1H NMR(500MHz,CDCl3) δ 10.56 (s, 1H), 8.93 (dd, J=10.2,5.4Hz, 1H), 8.84 (dd, J=
4.1,1.2Hz, 1H), 8.39 (dd, J=8.4,1.2Hz, 1H), 8.07 (dd, J=13.8,6.9Hz, 2H), 7.62-7.50 (m,
3H), 7.45 (dd, J=8.4,4.1Hz, 1H), 7.28 (dd, J=7.7,5.3Hz, 1H)13C NMR(126MHz,CDCl3)δ
165.11,149.08,138.99,134.88,131.84,131.52,131.56,130.32,128.76,127.18,121.50,
121.33,116.36,114.84.
Embodiment 18: preparation N- (5- nitrine quinoline -8- amino) benzamide
0.1mmol N- (- 8 amino of quinoline) benzamide (II -1) is added to the N,N-dimethylformamide and 5ml of 5ml
Mixed liquor 10ml is made in deionized water, 0.3mmol sodium azide, copper bromide 0.03mmol, 0.3mmol over cure are added thereto
Sour potassium, 0.1mmol DBU, 0.1mmol TBAB, 40 DEG C are reacted 12 hours, and saturation NaCl is added after reaction, in reaction solution
Aqueous solution is extracted with dichloromethane, and takes organic layer dry by anhydrous magnesium sulfate, filtering, 60 DEG C of decompression distilleds to remove solvent, i.e.,
Obtain crude compound shown in the formula (I -1).It is 1:5 with volume ratio by crude compound shown in formula (I -1) into silica gel column chromatography
Ethyl acetate and petroleum ether solution be mobile phase, TLC tracking collect Rf value be 0.3-0.5 eluent, collect
Solvent is removed under reduced pressure in eluent, dry, obtains formula (I -1) compound represented sterling 16mg.
1H NMR(500MHz,CDCl3) δ 10.56 (s, 1H), 8.93 (dd, J=10.2,5.4Hz, 1H), 8.84 (dd, J=
4.1,1.2Hz, 1H), 8.39 (dd, J=8.4,1.2Hz, 1H), 8.07 (dd, J=13.8,6.9Hz, 2H), 7.62-7.50 (m,
3H), 7.45 (dd, J=8.4,4.1Hz, 1H), 7.28 (dd, J=7.7,5.3Hz, 1H)13C NMR(126MHz,CDCl3)δ
165.11,149.08,138.99,134.88,131.84,131.52,131.56,130.32,128.76,127.18,121.50,
121.33,116.36,114.84.
Embodiment 19: preparation N- (5- nitrine quinoline -8- amino) benzamide
0.1mmol N- (- 8 amino of quinoline) benzamide (II -1) is added to the N,N-dimethylformamide and 5ml of 5ml
Mixed liquor 10ml is made in deionized water, 0.3mmol sodium azide, copper acetate 0.03mmol, 0.3mmol dioxy are added thereto
Change manganese, 0.1mmol DBU, 0.1mmol TBAB, 40 DEG C are reacted 12 hours, and saturation NaCl is added after reaction, in reaction solution
Aqueous solution is extracted with dichloromethane, and takes organic layer dry by anhydrous magnesium sulfate, filtering, 60 DEG C of decompression distilleds to remove solvent, i.e.,
Obtain crude compound shown in the formula (I -1).It is 1:5 with volume ratio by crude compound shown in formula (I -1) into silica gel column chromatography
Ethyl acetate and petroleum ether solution be mobile phase, TLC tracking collect Rf value be 0.3-0.5 eluent, collect
Solvent is removed under reduced pressure in eluent, dry, obtains formula (I -1) compound represented sterling 9mg.
1H NMR(500MHz,CDCl3) δ 10.56 (s, 1H), 8.93 (dd, J=10.2,5.4Hz, 1H), 8.84 (dd, J=
4.1,1.2Hz, 1H), 8.39 (dd, J=8.4,1.2Hz, 1H), 8.07 (dd, J=13.8,6.9Hz, 2H), 7.62-7.50 (m,
3H), 7.45 (dd, J=8.4,4.1Hz, 1H), 7.28 (dd, J=7.7,5.3Hz, 1H)13C NMR(126MHz,CDCl3)δ
165.11,149.08,138.99,134.88,131.84,131.52,131.56,130.32,128.76,127.18,121.50,
121.33,116.36,114.84.
Embodiment 20: preparation N- (5- nitrine quinoline -8- amino) benzamide
0.1mmol N- (- 8 amino of quinoline) benzamide (II -1) is added to the N,N-dimethylformamide and 5ml of 5ml
Mixed liquor 10ml is made in deionized water, 0.3mmol sodium azide, copper acetate 0.03mmol, 0.3mmol over cure are added thereto
Sour potassium, 0.1mmol triethylamine, 0.1mmol TBAB, 40 DEG C are reacted 12 hours, after reaction, saturation are added in reaction solution
NaCl aqueous solution, is extracted with dichloromethane, and takes organic layer dry by anhydrous magnesium sulfate, filtering, 60 DEG C of decompression distilleds removings molten
Agent is to get crude compound shown in the formula (I -1).By crude compound shown in formula (I -1) into silica gel column chromatography, with volume ratio
It is mobile phase for the ethyl acetate of 1:5 and the solution of petroleum ether, TLC tracking is collected the eluent that Rf value is 0.3-0.5, collected
To eluent solvent is removed under reduced pressure, it is dry, obtain formula (I -1) compound represented sterling 6mg.
1H NMR(500MHz,CDCl3) δ 10.56 (s, 1H), 8.93 (dd, J=10.2,5.4Hz, 1H), 8.84 (dd, J=
4.1,1.2Hz, 1H), 8.39 (dd, J=8.4,1.2Hz, 1H), 8.07 (dd, J=13.8,6.9Hz, 2H), 7.62-7.50 (m,
3H), 7.45 (dd, J=8.4,4.1Hz, 1H), 7.28 (dd, J=7.7,5.3Hz, 1H)13C NMR(126MHz,CDCl3)δ
165.11,149.08,138.99,134.88,131.84,131.52,131.56,130.32,128.76,127.18,121.50,
121.33,116.36,114.84.
Embodiment 21: anti-malarial detection
It selects using FCCSM/YN plant of the malignant malaria original that Yunnan Institute of Parasitic Diseases saves as worm sources reference Sun Yuanhong
Deng method (the external training of the Yunnan Province Sun Yuanhong, Zhou Jialian, Liu Hui, Wang Hengye, Yang Henglin Plasmodium falciparum naphthols quinoline strain
Educate [J] China Pathogen Biology magazine, 2010,02:124-126-133. and Li Yu, Chen Hua, Yang Henglin naphthols quinoline be applied alone and
It inhibits plasmodium falciparum Effect study [J] China Pathogen Biology magazine, 2011,07:505- with external with azithromycin 5
506-520.) culture obtains the test that plasmodium falciparum naphthols quinoline resistant strain is used for pharmaceutical activity.
Pharmaceutical activity test 00 μ l of cultivating system total volume used, the above-mentioned resistant strain of volumetric concentration 1%, normal person are red thin
Born of the same parents' hematocrit 1%, normal person's AB type serum content are 10%, set 5%CO2Culture in 37 DEG C of insulating boxs of gas.By embodiment 1-14
The compound (I-1) of preparation-compound (I-14) volumetric concentration 1% DMSO aqueous solution is configured to 10 μM of drug to be measured 1
~14.
Drug 1~14 to be measured is added into cultivating system respectively again, drug concentration is made in cultivating system to be respectively 0.01,
0.1, five parallel groups are arranged in 1,10.0,100.0 μM of five concentration gradient, each concentration gradient, cultivate 24 hours, take at 37 DEG C
Sample.Replace drug to be measured for control with isometric PBS (pH is by 7.4).The suppression result that drug to be measured grows malaria worm passes through
Drug and the culture medium that drug is not added, the external microdetermination of Rieckmann recommended using WHO are added on more same plate
Method is (referring to Riekmann KH, S ax LJ, Cambell GH, et al.Dru g sensitivity of p lasmod ium
Fa lcip arum.An in vitro microtech nique [J] .Lancent, 1978,1:22-3. and Wang Hengye, Yang Heng
Woods plasmodium falciparum drug susceptibility external test method progress [J] China Pathogen Biology magazine, 2009,4 (7):
552-5.).Resistant strain plasmodium falciparum is cultivated according to the above method to the small ring bodies of plasmodium (small trophozoite) be it is main when, use
5% sorbierite synchronization process, second generation plasmodium falciparum after processing (about 30h, ring bodies sync rates up to 95% or more) use " O " type
It is 10000~50000/μ l blood that human red blood cells, which are diluted to density, and the ratio between blood containing worm and culture medium are 1:5, is mixed, to assay plate
50 μ l worm blood-culture medium suspension (every kind of drug measures 2 rows simultaneously) is successively added in each well (from low concentration to high concentration), is put into
It in candle cylinder, is cultivated for 24 hours in (37 ± 1) DEG C insulating box, advance control well, when 60% or more ring bodies is developed to schizont
(28~36h) stops culture, takes blood film, dyeing, microscopy, every well counts the schizont number in 200 phorozoons, to 50% malaria
Disease worm grows 503nhibiting concentration (IC50) and is handled with ICEstimator software software, calculates IC50 and IC50 95%
Credibility interval, standard deviation are the standard deviations of several independent experiments, the results are shown in Table 1, are control with 8- aminoquinoline.DMSO's
Concentration is no more than always 0.1% while also not inhibiting the growth of malaria worm.
Table 1, Compound ira vitro anti-malarial activity
Embodiment 22: antitumor detection
Tumour cell A549, HePG-2 are inoculated with 4000 cell/bottles to the DMEM high containing 10% fetal calf serum respectively
In the Tissue Culture Flask of soup culture solution, it is placed in 5%CO2, cultivate 3 days in 37 DEG C of incubator, take out Tissue Culture Flask sterile
Cell is collected in station.Cell is seeded to the DMEM soup-stock culture containing 10% fetal calf serum with the concentration in 4000/hole
In 96 orifice plates of liquid, and cover in plate plus annotation, in 5%CO2, 37 DEG C culture 12 hours, it is adherent on 96 orifice plates to cell,
In aseptic operating platform with rifle add drug to be measured (embodiment 1-14 preparation compound (I-1)-compound (I-14) make every hole medicine
Object concentration is respectively 0.01,0.1,1,10.0,100.0 μM of five concentration gradient, and there are five parallel groups for each concentration setting, with 8-
Aminoquinoline is control), and 96 orifice plates are placed in 5%CO again2, 37 DEG C culture 24 hours.96 orifice plates are taken out, into each hole
The MTS reagent box reagent (purchased from Promega company) of 20 μ L is added, is protected from light hatching 40 minutes, surveys its absorbance using microplate reader.
To calculating cell inhibitory rate and cytotoxicity, handled with ICEstimator software software, calculate IC50 and
95% credibility interval IC50, the results are shown in Table shown in 2.
Table 2, Compound ira vitro anti-tumor activity
Claims (10)
1. 8- aminoquinolines shown in a kind of formula (I),
R in formula (I)1Replace alkyl, institute for phenyl, substituted-phenyl, cyclohexyl, C1-C10 alkyl, C1-C10 alkoxy or C1-C10
The substituent group for stating substituted-phenyl is methyl, chlorine, nitro, fluorine or methoxyl group；The C1-C10 replaces the substituent group of alkyl to be N-
Fmoc-；
R2For H or methyl；
R3For-N3、-NH2OrR4For phenyl, C5 aromatic ring or C1-C10 alkyl；R1For phenyl, R2For hydrogen, R3For NH2's
Except compound.
2. 8- aminoquinolines as described in claim 1, it is characterised in that the R1For phenyl, aminomethyl phenyl, to first
Base phenyl, rubigan, p-nitrophenyl, o-fluorophenyl, p-methoxyphenyl, C4 alkoxy or C4 replace alkyl, described to take
Dai Jiwei N-Fmoc-.
3. 8- aminoquinolines as described in claim 1, it is characterised in that the compound is one of following:
4. the preparation method of 8- aminoquinolines described in a kind of claim 1, it is characterised in that work as R3For-N3When, it is described
Method are as follows: compound n,N-Dimethylformamide shown in formula (II) and water are dissolved, nitrine source, oxidant and copper catalysis is added
Agent constitutes reaction system, and saturation NaCl aqueous solution is added after 40 DEG C of fully reactings, in reaction solution, is extracted with dichloromethane, has taken
Machine layer is dry by magnesium sulfate, filter, solvent is evaporated off to get crude product in rotation under room temperature；By crude product into silica gel column chromatography, with volume
Solution than ethyl acetate and petroleum ether for 1:3-10 is mobile phase, and the eluent that Rf value is 0.3-0.5 is collected in TLC tracking,
It collects obtained eluent and solvent is removed under reduced pressure, it is dry, obtain 8- aminoquinolines shown in formula (I)；The nitrine
Source is sodium azide or trimethyl silane nitrine；The oxidant is potassium peroxydisulfate or manganese dioxide；The copper catalyst is vinegar
Sour copper, cuprous iodide, copper bromide, copper chloride or stannous chloride；
R in formula (I)1Replace alkyl, institute for phenyl, substituted-phenyl, cyclohexyl, C1-C10 alkyl, C1-C10 alkoxy or C1-C10
The substituent group for stating substituted-phenyl is methyl, chlorine, nitro, fluorine or methoxyl group；The C1-C10 replaces the substituent group of alkyl to be N-
Fmoc-；
R2For H or methyl；
R3For-N3；
R in formula (II)1R in same formula (I)1, R2R in same formula (I)2。
5. the preparation method of 8- aminoquinolines as claimed in claim 4, it is characterised in that the N, N- diformazan
Base formamide volumetric usage is calculated as 1~50ml/mmol with the amount of combinations of materials shown in formula (II), the volumetric usage of the water with
The amount of combinations of materials shown in formula (II) is calculated as 1~50ml/mmol, the nitrine source, oxidant, copper catalyst and formula (II) institute
Show that the ratio between amount of combinations of materials is 1~5:1~6:0.01~1:1.
6. the preparation method of 8- aminoquinolines as claimed in claim 4, it is characterised in that in the reaction system also
Added with auxiliary agent and phase transfer catalyst, the auxiliary agent is one of following: acetic acid, potassium carbonate, triethylamine or 1,8- diaza two
11 carbon -7- alkene of ring；The phase transfer catalyst is tetrabutylammonium bromide, the auxiliary agent, phase transfer catalyst and formula (II) institute
Show that the ratio between amount of combinations of materials is 0.1~2:0.5~3:1.
7. the preparation method of 8- aminoquinolines described in a kind of claim 1, it is characterised in that work as R3For-NH2When, institute
State method are as follows: (1) compound n,N-Dimethylformamide shown in formula (II) and water are dissolved, nitrine source, oxidant, copper is added
Catalyst and/or auxiliary agent and phase transfer catalyst constitute reaction system, and after 40 DEG C of fully reactings, saturation is added in reaction solution
NaCl aqueous solution, is extracted with dichloromethane, take under organic layer dry by magnesium sulfate, filtering, room temperature rotation be evaporated off solvent to get
Crude product；It is the ethyl acetate of 1:3-10 and the solution of petroleum ether as mobile phase using volume ratio by crude product into silica gel column chromatography, TLC
The eluent that Rf value is 0.3-0.5 is collected in tracking, and solvent is removed under reduced pressure in the eluent collected, dry, obtains compound；
The nitrine source is sodium azide or trimethyl silane nitrine；The phase transfer catalyst is tetrabutylammonium bromide, the auxiliary agent
It is one of following: acetic acid, 11 carbon -7- alkene of potassium carbonate, triethylamine or 1,8- diazabicylo；The oxidant is potassium peroxydisulfate
Or manganese dioxide；The copper catalyst is copper acetate, cuprous iodide, copper bromide, copper chloride or stannous chloride；(2) by step (1)
Prepare compound tetrahydrofuran and water dissolution, add NaHS, react 4 hours under room temperature, are added into reaction solution full
It with NaCl aqueous solution, is extracted with dichloromethane, takes rotation under organic layer dry by magnesium sulfate, filtering, room temperature that solvent is evaporated off, i.e.,
Crude product is obtained, crude product is subjected to silica gel column chromatography, is the ethyl acetate of 1:3 and the solution of petroleum ether as mobile phase using volume ratio, TLC
The eluent that Rf value is 0.3-0.5 is collected in tracking, and solvent is removed under reduced pressure in the eluent collected, dry, obtains formula (I) institute
Show 8- aminoquinolines；The amount for the combinations of materials that the tetrahydrofuran volumetric usage is prepared with step (1) is calculated as 1~
50ml/mmol, the amount for the combinations of materials that the water volume dosage is prepared with step (1) are calculated as 1~50ml/mmol, the sulphur
The ratio between sodium hydride and the amount of combinations of materials of step (1) preparation are 1~5:1；
R in formula (I)1To replace alkyl for phenyl, substituted-phenyl, cyclohexyl, C1-C10 alkyl, C1-C10 alkoxy or C1-C10,
The substituent group of the substituted-phenyl is methyl, chlorine, nitro, fluorine or methoxyl group；The C1-C10 replaces the substituent group of alkyl to be N-
Fmoc-；
R2For H or methyl；
R3For-NH2；
R in formula (II)1R in same formula (I)1, R2R in same formula (I)2。
8. the preparation method of 8- aminoquinolines described in a kind of claim 1, it is characterised in that work as R3ForR4
When for phenyl, C5 aromatic ring or C1-C10 alkyl, the method are as follows: (1) by compound N, N- dimethyl formyl shown in formula (II)
Amine and water dissolution, addition nitrine source, oxidant, copper catalyst and/or auxiliary agent and phase transfer catalyst composition reaction system, 40
Saturation NaCl aqueous solution is added after DEG C fully reacting, in reaction solution, is extracted with dichloromethane, takes organic layer dry by magnesium sulfate
Solvent is evaporated off to get crude product in rotation under dry, filtering, room temperature；It is the acetic acid of 1:3-10 with volume ratio by crude product into silica gel column chromatography
The solution of ethyl ester and petroleum ether is mobile phase, and the eluent that Rf value is 0.3-0.5, the eluent collected are collected in TLC tracking
Solvent is removed under reduced pressure, it is dry, obtain compound；The nitrine source is sodium azide or trimethyl silane nitrine；The phase turns
Shifting catalyst is tetrabutylammonium bromide, and the auxiliary agent is one of following: acetic acid, potassium carbonate, triethylamine or 1,8- diazabicylo
11 carbon -7- alkene；The oxidant is potassium peroxydisulfate or manganese dioxide；The copper catalyst is copper acetate, cuprous iodide, bromination
Copper, copper chloride or stannous chloride；(2) step (1) prepare compound tetrahydrofuran and water are dissolved, adds phenylacetylene, copper
Catalyst reacts 12 hours under room temperature, and saturation NaCl aqueous solution is added into reaction solution, is extracted with dichloromethane, takes organic layer
Solvent is evaporated off to get crude product in rotation under, filtering dry by magnesium sulfate, room temperature, and crude product carries out silica gel column chromatography, with ethyl acetate
The solution that volume ratio with petroleum ether is 1:4 is mobile phase, and the eluent that Rf value is 0.3-0.5 is collected in TLC tracking, and collection obtains
Eluent solvent is removed under reduced pressure, it is dry, obtain 8- aminoquinolines shown in formula (I)；The copper catalyst is vinegar
Sour copper, cuprous iodide, cuprous bromide or copper chloride；The tetrahydrofuran volumetric usage is with step (1) prepare compound substance
Amount be calculated as 1~50ml/mmol, the water volume dosage is calculated as 1~50ml/ with the amount of step (1) prepare compound substance
Mmol, the ratio between the phenylacetylene, amount of copper catalyst and step (1) prepare compound substance are 0.8~2:0.01~1:1；
R in formula (I)1Replace alkyl, institute for phenyl, substituted-phenyl, cyclohexyl, C1-C10 alkyl, C1-C10 alkoxy or C1-C10
The substituent group for stating substituted-phenyl is methyl, chlorine, nitro, fluorine or methoxyl group；The C1-C10 replaces the substituent group of alkyl to be N-
Fmoc-；
R2For H or methyl；
R3ForR4For phenyl, C5 aromatic ring or C1-C10 alkyl；
R in formula (II)1R in same formula (I)1, R2R in same formula (I)2。
9. 8- aminoquinolines described in a kind of claim 1 are preparing the application in anti-malaria medicaments.
10. 8- aminoquinolines application in preparation of anti-tumor drugs described in a kind of claim 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610640635.7A CN106349160B (en) | 2016-08-05 | 2016-08-05 | A kind of 8-aminoquinoline derivatives and its preparation and application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610640635.7A CN106349160B (en) | 2016-08-05 | 2016-08-05 | A kind of 8-aminoquinoline derivatives and its preparation and application |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106349160A CN106349160A (en) | 2017-01-25 |
| CN106349160B true CN106349160B (en) | 2019-07-26 |
Family
ID=57843703
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610640635.7A Active CN106349160B (en) | 2016-08-05 | 2016-08-05 | A kind of 8-aminoquinoline derivatives and its preparation and application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106349160B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108250135A (en) * | 2018-01-19 | 2018-07-06 | 浙江工业大学 | A kind of preparation method of naphthylamine derivative |
| CN111057077B (en) * | 2019-12-31 | 2023-04-07 | 安庆师范大学 | Sulfonic acid zinc metal organic complex and application thereof |
| CN114591297B (en) * | 2022-03-15 | 2023-08-08 | 浙江工业大学 | Maleimided derivative containing tryptophan polypeptide and preparation method and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040087548A1 (en) * | 2001-02-27 | 2004-05-06 | Salvati Mark E. | Fused cyclic succinimide compounds and analogs thereof, modulators of nuclear hormone receptor function |
| CN103254141A (en) * | 2013-04-26 | 2013-08-21 | 浙江工业大学 | 4-[4-(2-dipropylamino acetamido) phenylamino]-6-substituted quinazoline compound as well as preparation method and application thereof |
| CN103254143A (en) * | 2013-04-26 | 2013-08-21 | 浙江工业大学 | 4-[4-(2-diethylamino acetamido)phenylamino]-6-(substituted methoxyl)formylamino quinazoline compound as well as preparation method and application thereof |
-
2016
- 2016-08-05 CN CN201610640635.7A patent/CN106349160B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040087548A1 (en) * | 2001-02-27 | 2004-05-06 | Salvati Mark E. | Fused cyclic succinimide compounds and analogs thereof, modulators of nuclear hormone receptor function |
| CN103254141A (en) * | 2013-04-26 | 2013-08-21 | 浙江工业大学 | 4-[4-(2-dipropylamino acetamido) phenylamino]-6-substituted quinazoline compound as well as preparation method and application thereof |
| CN103254143A (en) * | 2013-04-26 | 2013-08-21 | 浙江工业大学 | 4-[4-(2-diethylamino acetamido)phenylamino]-6-(substituted methoxyl)formylamino quinazoline compound as well as preparation method and application thereof |
Non-Patent Citations (4)
| Title |
|---|
| A First Example of Cobalt-Catalyzed Remote C-H Functionalization of 8-Aminoquinolines Operating through a Single Electron Transfer Mechanism;Christopher J. Whiteoak,等;《Advanced Synthesis & Catalysis》;20160415;第358卷(第10期);第1679-1688页尤其是第1685页方案3 * |
| Conghui Tang,等.Copper-Catalyzed C−H Azidation of Anilines under Mild Conditions.《Journal of the American Chemical Society》.2012,第134卷第18924-18927页. * |
| Copper-catalysed regioselective azidation of arenes by C–H activation directed by pyridine;Chandra S. Azad,等;《RSC Advances》;20151116;第5卷;第100223-100227页 * |
| Indirect C-H Azidation of Heterocycles via Copper-Catalyzed Regioselective Fragmentation of Unsymmetrical λ3-Iodanes;Dmitrijs Lubriks,等;《Journal of the American Chemical Society》;20120822;第134卷(第37期);第15436-15442页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106349160A (en) | 2017-01-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104540836B (en) | Ring as arginase inhibitor retrains analog | |
| Carlos Klein-Junior et al. | Indole alkaloids and semisynthetic indole derivatives as multifunctional scaffolds aiming the inhibition of enzymes related to neurodegenerative diseases–a focus on Psychotria L. genus | |
| CN105153142B (en) | The Furazan Derivatives and antitumor activity of cumarin parent nucleus | |
| CN106349160B (en) | A kind of 8-aminoquinoline derivatives and its preparation and application | |
| Arshad et al. | Syntheses, in vitro evaluation and molecular docking studies of 5-bromo-2-aryl benzimidazoles as α-glucosidase inhibitors | |
| CN106632383A (en) | Curcumenol derivative as well as preparation method and application thereof in antitumor drugs | |
| CN107235902A (en) | The licochalcone A pyrazoline analog derivative and its synthetic method of one class tool antitumor activity | |
| US20140315959A1 (en) | Treatment of ovarian cancer with benzylidenebenzohydrazides | |
| CN104926814A (en) | Matrine derivative and application thereof | |
| CN108084177B (en) | A kind of jamaicin 9- pyrazole derivatives and its preparation and application | |
| CN107011170B (en) | Fucoxanthin derivative and preparation method and application thereof | |
| CN105367575B (en) | A kind of folacin compound, its preparation method and medical usage | |
| CN102617521A (en) | Gamma-butyrolactone polyketone compounds having antineoplastic activity | |
| CN108530436B (en) | Pyrazole compound and preparation method and application thereof | |
| CN105541943A (en) | Berberine-baicalin compound and preparation method and application thereof | |
| CN109516959A (en) | 2- fragrant amino -4- substituted uracil derivative and its application in preparation of anti-tumor drugs | |
| JP2009286705A (en) | Alkylcoumarins of new antitumor substance and use thereof | |
| CN108285424B (en) | Gossypol Schiff base derivative, preparation and application thereof in resisting plant tobacco mosaic virus | |
| CN109776551A (en) | Dioxanes and quinazoline derivant preparation method | |
| CN102627625A (en) | Schizandrin, schisanhenol and schisandrin-b derivates and application thereof | |
| CN105294639B (en) | A kind of asymmetric New cyclobutane derivative and its preparation method and application | |
| CN104926804B (en) | One kind has compound, the preparation method and use of antitumor action | |
| CN114315685A (en) | Cyanoguanidine derivative, preparation method thereof and anti-tubercle bacillus drug | |
| CN114369076A (en) | Two indene compounds in purslane and extraction and separation method thereof | |
| CN101735189A (en) | Preparation method, preparation and application of tricin |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |